Diamide-based sulfonamide derivatives as new urease inhibitors: Synthesis, biological evaluation, and computational studies.

Sulfonamide is a well-recognized bioactive functional group in medicinal chemistry that has gained significant attention owing to its broad application potential in this field. In this work, a new series of diamide-based sulfonamide derivatives, compounds 10a-g and 11a-e, was specifically designed as urease inhibitors and synthesized via the reaction of azlactone derivatives with 4-aminobenzenesulfonamide. The structures of the synthesized compounds were confirmed using 1H and 13C NMR spectroscopy, FT-IR spectroscopy, CHN elemental analysis, and LC-MS. Interestingly, all synthesized derivatives displayed outstanding urease inhibitory activity, with IC50 values in the low micromolar range (IC50 values ≤0.71 μM), demonstrating potency far superior to that of the reference inhibitor thiourea (IC50 value = 21.34 μM). To elucidate the binding mechanism, molecular docking and molecular dynamics (MD) simulations were performed on the most potent compound (10a), which further confirmed stable and favorable interactions with the enzyme's active site, particularly with the catalytic nickel center and key residues. Additionally, in silico pharmacokinetic profiling predicted promising drug-like characteristics for the most active compound. Density functional theory (DFT) calculations provided insights into the electronic structures and reactivity descriptors of these compounds. The combined experimental and computational data firmly establish this novel sulfonamide series as a highly potent and promising class for the development of anti-urease agents in future.